Hydroiodides of amino esters of penicillin and oil composition thereof



United States PatentO HYDROIODIDES OE AMINO ESTERS OF PENI- CILLIN AND OIEGOMPOSITION THEREOF Erling Knud Frederiksen, Holte, and Erling Juhl Nielsen, Charlottenlund, Denmark, assignors to Love'ns kemiske -Fa'brik ved A. Kongstecl, Copenhagen, Denmark, a firm Nos Drawing. Application. November -27, .1951,

w'Serial' NU-2585511 Claims priority, applicationDenmark July 7;1'949 17'.-Claims.' (CL-167 65) This invention'relatesto dilficultysoluble-hydroiodides of amino iestersofpenicillin and to injectable-and other compositions comprising particles of the said salts in suspension in a suitable carrier.

This application is -a.,continuation-in-part of our copending applications Seria'l'Nos. 168,384 filed June 15,

. 1950,.and 246,148,.filedSepternber l1, 1 951 (now abancloned), the latter application being atcontinuation-inpart of the former.

' One object of the present invention is to provide novel penicillin compounds which possess advantageous: antilkbioticaproperties. Being'difliculty soluble these .com-' -pounds are advantageous inthat a protracted penicillin r eifect is obtained. Furthermore, in' the' use oftheesters of the: invention penicillin accumulates in certain of;the

1 body tissues and fluids, for example-in the lungs, brain and spinal Efiuid. Suchv accumulation'provides a high concentration of penicillin which is effective therapeutically in wthe treatment of "the infectedportion of -the-body. The

...compounds are, furthermore, advantageous in the treatment of patients who cannot stand the action of metal -.salts (certain heart diseases) -and .whocannot, therefore,

:.- stand .treatment with," for.v instance-,1 sodium-penicillin.

Another object ofathevinvention is toaprovide"for: an

L injectablezcompiosition; comprisinga difliculty soluble hy- -l droiodide of a dialkylaminoalkyli ester: of: penicillin in a vegetable or-animaloil; to which'a small amount,'..sayfl to "3 per cent, of a salt',-particularly a-basicssalt, of aluminium wand a'lipophilic acid,.such as .stearici acid, :may bezadded.

.Thereby the. penicillin tetfect .can be: further :protracted. Further-objects of :theinvention a will :appear' from :the

'- following, .where r a: more: detailed. description oftour. in-

1- .vention is given :togethenwitlr results of clinicalxtests with .ucompounds of the invention andxfurtheritheiinvention is illustrated by examples showing.atconvenientrmethod of preparing said compounds, but we wish it to be understood that our invention lSi notto be considered limited thereby.

Some of the salts of the invention form crystals, while others form amorphous bodies;but in either case the salts have a full antibacterial eifect corresponding to that of the content'of'penicillin.

- The compounds of thepresentinvention'are the 'hydro- 1 iodide salts of aminoalcohol esters ofpenicillimrrepre- 'sented by the following formula:

.yalkyl groupsrcontaining from 1 to .12'carbon=atoms. Genzerally the total number of2carbon atoms in R,'-R 1-'and R2 will not exceed 28, and in most instances, it will'bepre- "ferred to limit the total-number of"carbon=atoms in -R to cess of.28.

It has been found thatwhe'n the 'alkylene bridge contains from 2 to 5 carbon atoms with-'not more than 4 *carbon atoms in the 'alkyl substituents'attached to'the carbonatoms of the bridge'andwhen'the total. number of v carbon atoms in R, R1 and R2 does not exceed 1 8;"comrother :compounds of the invention; result.

Because of their superior therapeuticwproperties,z-the preferred compounds of the present invention are those in which R is an alkylene bridge of 2 to 4 carbon atoms in vwhich there: are. attached to'the carbon atornsthereof, in addition to Pen-COO and N, radicals selected from the group consisting of hydrogen and alkyl groups, the number of carbon atoms in such alkyl groups not exceeding 4, preferably not exceeding 2, and in which R1 and R2 contain from 1 to 8 carbon atoms. In such compounds where R1 and R2 contain from 1 to 4 carbon atoms, an increase in desirable properties ofv the compounds has been noted.

The compounds of the present invention which are char- .acterised by the greatest 'ability tov provide high antibiotic properties'and high accumulation in the lungs are those in which R is an unsubstituted alkylene bridge containing 2 to 3 carbon atoms and where R1 and R2 are alkyl groups containing from 1 to 3 "carbonatoms;'f0r"examp1e, the

dimethyl-,rnethylethyl'- and diethyl=aminoethylester;the di-propyl (either 11 or iso aminoethyl ester; the methylpropyl or ethylpropyl (either nor iso-) aminoethyl ester and the corresponding aminopropyl esters, such as d1- 'methylaminopropyl "'ester and the diethylaminopropyl "I ester etc.

" 'Itwill be notedthat in the above'formula'the above bridges are'connected atthe left with" the acyloxy residue of'the penicillinand at the right'with' the nitrogen atom;

thus the carbon atom at the left ofthe ethylene bridge is designated as 2 and the one at the right as 1; whereas in the octylene bridge the carbon atoms'reading from left to .right are designated 8, 7, 2, 1, respectively, and the same is true of the other bridges.

From the above formula, it will be 'notedthat inthe particular-compounds, the R1 and Rzgroups may be the same ordiiferent and that these groups may be 'preslent incompounds having the various bridgesdefined by R. While the'preferred esters-will be the esters of benzylrpenicillin (penicillin'G) and such esters'will be more'spe- "cifically referred to herein',ithe penicillin residue in" the compound may, if desired, be that of any other penicillin,

I for example, penicillin O, K, F," dihydro-F and X, as well the bridge is ethylene,

.. methylethylene, dihexylethylene, methyloctylene or di-npropyloctylene; and those in-which the R1 and R2 groups -vary from methyl to dodecyl; for example, dimethyl,

.butyloctyl,di-dodecyl. The typical compounds are also illustrated by the specificexamples. ""Thecompounds of the invention may be prepared by any suitable method. 1 Advantageously, when the .alkylene bridge contains 2, to '4carbon atoms, where the .carbon atom. next to oxygen has at least one unsubstituted .hydrogen atom, the esters are penicillin salt and a, halide of .responding totheester .desired, .such .halide being pre- .paredalcohol by well-known procedures. .i

, agent in which theester formed is soluble, such prepared by reacting a 'the tr'ialkylamine corif desired, from the corresponding amino- For. example, a penicillinsaltis suspended or dissolvedv in a suitable diluting as one of-thelower alcohols,.for instance methanol, .ethanol or isopropanoltaketone such as acetone, methylethyl ketone,

di-isopropyltketonetand.acetlyacetone; and hydrocarbon 1 10 with a total of carbonatoms in R, Ri-and Rz-not in-ex- 7 such as benzene,.:toluene, xylene; chlorinated hydrocar- Hbons. such asnchloroform and carbon tetrachlorideydi- .methyl and diethylacetamide, o'r,=tetrahydrofuran and the like. "The halide may then: be-added, preferably in excess, .forexample 5l0. per 'centiexcess, after which the .mixture isallowed toreact -.under,1 agitation by stirring or shaking, if .desired. iThe temperature at which the reaction takes placenmay be varied as desired, so long as it is :notsufficiently high to vcausedecomposition of the penicillin salt or. thepenicillin ester formed. Generally, thereaction will. be conducted between about room temperature, although it may be lower, and about 3 80 C. to 90 C. Preferably, the reaction is conducted under reflux at a temperature between about 40 C. and about 70 C., under which conditions good yields of 1tlhe product will generally be obtained in from /2 to 5 ours.

The reaction may be illustrated by the following reaction using sodium penicillin and diethylaminoethyl chloride as typical:

The sodium chloride or other salt formed by the reaction is removed by filtration or other suitable means. The hydroiodide may be formed directly by adding an alcoholic solutton ot' hydroiodic acid. The hydroiodide is then precipitated, preferably by adding water. lreterably, however, the solution of the ester is treated with an acid which forms a water-soluble salt of the ester, preferably an alcoholic solution of hydrochloric acid. 'lherearter, an aqueous solution of a water-soluble iodide is added to the solution of the soluble salt of the ester which may previously have been diluted with water. The diliicultly water-soluble hydroiodide of the penicillin ester precipitates and is removed from the solution by filtering, decanting, centrifuging or the like. of soluble iodides are potassium, sodium, ammonium and calcium iodides.

In place of the sodium salt of penicillin given as an example in the above equation any soluble or insoluble penicillin salt may be employed for example the potassium, ammonium, calcium, barium, silver, procaine, triethylamine or N-ethyl-piperidine salt. Instead of employing the chloride of the tertiary amine, the other halides may be used, particularly the bromide.

The above method for producing the penicillin esters is not claimed herein, but is the subject matter of our co-pending application Serial No. 258,513, filed November 27, 1951.

Furthermore, certain of the penicillin esters and the soluble salts thereof form the subject matter of our copendliig application Serial No. 258,512, filed November 27, 51.

In place of reacting the penicillin salt with the halide of the tertiary amine, the compounds of the present invention may be produced by reacting penicillin anhydride or a mixed anhydride of penicillin and acetic acid directly with the aminoalcohol corresponding to the ester desired. The mixed anhydride is prepared by reacting a penicillin salt in a suitable organic solvent with acetyl chloride at room temperature or slightly lower, for instance 5C. to C. The mixed anhydride in the solution is then reacted with aminolacohol at about the same term perature, the solution is evaporated to form a syrup, the residue is washed with petroleum ether, for example, and then extracted with a solvent, such as absolute ethanol. After removal of the chloride (formed by the cation of the penicillin salt and chlorine from the acetyl chloride) by filtration or in any other suitable manner, the ester is converted into a water-soluble salt such as the hydrochloride or citrate, and this again is converted to the difiicultly soluble hydroiodide by the methods described above in connection with the production of the hydroiodides from the salt of penicillin and the halide of the tertiary amine. The method involving the use of penicillin anhydride is described in I. A. C. S. 70, pages 2964-2966 (1948).

Important properties characteristic of the new substances of the present invention are illustrated by the following biological tests which were carried out with oenicillin-diethylaminoethyl ester-hydroiodide suspended in an aoueous carboxymethyl cellulose-phosphate mixture (called Preparation A hereinafter).

300,000 units of Preparation A were injected subcutaneously in 10 persons and 300,000 units of procaine- Examples penicillin were injected in 10 other persons and in each case the concentration of penicillin in the blood in units per cc. was determined after 2, 12 and 24 hours. The results of these determinations are given in Table I.

TABLE I Preparation A Concentration in blood 2 hours 12 hours 24 hours 1st person 0.52 0. 02 0 0. 17 0.18 0. 02 0.42 0.15 0 0.29 0. 12 0.02 0. 52 0.15 0.08 0. 44 0. 27 0.1 0. 30 0.08 0. 02 0. 28 0. 04 0. 02 0. 44 0. 26 0 10th person 0. 39 0. 04 0 Average 0. 38 0. 13 0. 026

Procaine-penicillin Concentration in blood 2 hours 12 hours 24 hours 1st person 0.15 0.10 0.02 2d person.-. 0. 4 0.13 0. 02 3d person... 0.36 0. 16 0.07 4th person 0. 48 0. 25 0.1 5th person... 0.18 0.16 0.13 Mb person. 0. 61 0.23 0. [)6 7th person.- 0.80 0. 13 0.05 0. 46 0. 29 0.17 0.75 0.11 0.02 0. 7 2 0. 28 0. 08

Average 0. 49 0. 18 0. 07

The concentrations given are about 20 per cent below the actual concentrations, due to the restrictive efiect of serum on the elfect of penicillin.

It will be seen from the tables that after 2 and 12 as well as after 24 hours, Preparation A gives a conof 300,000 units of Preparation A in 5 persons. The

results are given in Table II.

TABLE II Preparation A Concentration in blood 1/2 hour 1 hour 1st person" 0.13 0. 41 2d person 0. 07 U. 13 3d person" 0.07 0.21 4th person.. 0.14 0.23 5th person 0. 21 0.33

Average 0. 12 0. 26

These tests show that Preparation A has a fairly good protracted efiect.

On the other hand further biological determinations of the penicillin concentration in various tissues show that in certain respects Preparation A is very superior to the hitherto known penicillin preparations, because it accumulates particularly in the lung tissue. This is demonstrated by the following.

25,000 units of Preparation A are dissolved in 2.5 ccs. of saline solution, and the solution was injected into a guinea-pig. In another guinea-pig 25,000 units of sodium benzylpenicillin in 2.5 ccs. of saline solution were injected. Both animals were killed /2 hour later, and the concentrations of penicillin were determined in the blood, the liver, the spleen and the lungs. The results are given in Table III.

With monogg gg stearate Stearate Hours after ln eetlon average Mam 8 lave" blood 15761 umts per cc. units per O. 43 0. 0 0. 72 1. 05 0. 68 0. 75 0. 51 0. 4O 0. 20 0.08 0. 0 0. O8 0 0. 05 0 The invention will be further illustrated by way of the following examples.

EXAMPLE 1.-BENZYLPENICILLIN-B-DIETHYLAMINO- ETHYL ESTER-HYDROIODIDE 7.44 kilograms of the potassium salt of penicillin are suspended in 40 liters of acetone (water content 1 to 1.7 per cent). 3 liters of diethylaminoethyl chloride are added, and the mixture is refluxed for /2. hour.

After cooling precipitated potassium chloride is removed by filtration, and the filtrate is evaporated in vacuum (70 to 80 mm. of mercury) until the temperature in the distillation vessel has raised to 30 to 35 C. Then the residue is poured into a mixture of 20 liters of water, 10 kilograms of ice and 1.28 liters of .85 per cent phosphoric acid.

Thereby a pale-yellow solution is obtained which is filtered under sterile conditions and cooled to 0 C. During 2-3 hours 40 liters of a sterile 20 per cent solution of potassium iodide are added with stirring. After addition the stirring is continued for another /2 hour at 0 C.

The crystalline precipitate of benZyL enicillin-fi-diethylaminoethyl ester-hydroiodide is separated from the liquid by filtration, washed with 10 liters of cold, sterile water and dried in vacuum at 40 C. The yield is from 9.5 to 10 kilograms.

EXAMPLE 2.BENZYLPENICILLIN-DIMETHYLAMINO- ETHYL ESTER-HYDROIODIDE 35.6 grams of the sodium salt of penicillin are suspended in 250 cc. of dry boiling acetone and 6.45 grams of dimethylaminoethyl chloride are added.

After refluxing for hour a further 3.2 grams of dimethylaminocthyl chloride are added and another 3.2 grams are added after 2 hours refluxing. This method is employed because the dimethylarninoethyl chloride polymerizes very easily.

After refluxing for 8 hours (total) the mixture is filtered, and the filtrate is evaporated in vacuum to a syrup.

The residue is triturated with petrol ether to remove excess of dimethylaminoethyl chloride and after this treatment it is dissolved in 200 cc. of anhydrous ethanol.

After addition of an alcoholic solution of hydrochloric acid (until a sample diluted with water shows pH:5) and 100 cc. of dry ether, the solution stands at 0 C. over night. On dilution of the solution with water and addition of 20 per cent more than the calculated amount of a potassium iodide solution the hydroiodide is obtained in a yield of 67 per cent and with M. P. 185-186 C.

EXAMPLE 3.-BENZYLPENICILLINMETHYLETHYL- AMINOETHYL ESTER-HYDROIODILE 7.4 grams of the potassium salt of benzylpenicillin are suspended in 40 cc. of acetone and 11.5 cc. of a solution of methylethylaminoethyl chloride in benzol containing 1.75 moles per liter are added. The mixture is refluxed for 3 hours. During this time potassium chlo- 8. ride separates which after refluxing of the mixture is removed by filtration. Then a solution of 4.2 grams of the monohydrate of citric acid in cc. acetone is added to the filtrate from the potassium chloride. The mixture is left standing at 0 C. for 2 hours, whereby benzylpenicillin-methylethylaminoethyl ester-citrate crystallizes therefrom. The yield of this substance Will be 8.75 grams corresponding to 73.5 per cent of the theoretically possible yield. The melting point of the citrate recovered in this manner is 76 to 79 C. 6.1 grams of thebenzylpenicillinmethylethylaminoethyl ester-citrate are dissolvedin 50 cc. of water and 17 cc. of a 10 per cent solution of .potassium iodide in water are added. The mixture is left standing at 0 C. for 2 hours during which time the hydroiodide of benzylpenicillin-methylethylami noethyl ester will crystallize. The crystallization product is recovered by filtration. The melting point of the benzylpenicillin-methylethylaminoethyl ester-hydroiodide recovered in this way is 180.5 to 181.5 C.

EXAMPLE 4:.BENZYLPENICILLIN-DI-N-PROPYL AMINOETHYL ESTER-HYDROIODIDE 7.4 grams of the potassium salt of penicillin are sus' pended in 40 cc. acetone and 3.3 grams di-n-propylaminoethyl chloride are added after which the mixture is refluxed for 2 hours. The potassium chloride formed in the refluxed mixture is then removed from the solution by filtration. Then a solution of 4.2 grams of the monohydrate of citric acid in 20 cc. acetone is added to the filtrate and the solution thus formed is diluted by cc. of water. To the diluted solution 33 cc. of a 10 per cent aqueous solution of potassium iodide are added. The mixture is left standing for 12 hours at 0 C. and the crystalline benzylpenicillin-di-n-propylaminoethyl ester-hydroiodide formed in the solution is then removed by filtration. The yield of the hydroiodide amounts to 8.15 grams which corresponds to 69 per cent of the theoretically possible yield. The melting point of the hydroiodide is 142 to 144 C.

EXAMPLE 5.BENZYLPENICILLIN-DI-N-BUTYLAMINO ETHYL ESTER-HYDROIODIDE 7.4 grams of the potassium salt of benzylpenicillin are suspended in 40 cc. of acetone and 3.8 grams di-nbutylaminoethyl chloride are added to the suspension. The mixture formed is then refluxed for 2 hours. After that it is subjected to distillation in vacuum in order to remove 20 cc. of the acetone contained in the mixture and the remainder is poured into 150 cc. of a mixture of ice and water, at the same time adding to the mixture such a quantity of 50 per cent phosphoric acid that the pH-value of the resulting solution will be 4.5. To the solution 40 cc. of a 10 per cent aqueous solution of potassium iodide are added and the mixture is left standing for 12 hours at 0 C. The benzylpenicillin-di-nbutylaminoethyl ester-hydroiodide thereby formed in the solution is removed therefrom by filtration, whereby a yield of 9.2 grams of this substance is recovered. This yield corresponds to 75 per cent of the yield theoretically possible. The melting point of benzylpenicillin-di-nbutylaminoethyl ester-hydroiodide is 61 C.

EXAMPLE 6.BENZYLPENICILLIN-DI-N-OCTYLAMINO- ET HYL ESTER-HYDROIODIDE A suspension of 7.4 grams of the potassium salt of benzylpenicillin in 40 cc. acetone is mixed with a solution of 6.1 grams of di-n-octylamiuoethyl chloride in 20 cc. benzol. The mixture is refluxed for 2 hours, whereby the penicillin salt and the organic chloride dissolve and potassium chloride separates which is then removed by filtration, whereafter the filtrate is evaporated in vacuo to form a syrup. This syrup is dissolved in 40 cc. of methanol and the equivalent amount of ethanolic hydrogen chloride is added to the solution which at the same time is subjected to cooling. A clear solution results to which 40 cc. of water are added and then 33 cc. of a 10 per cent solution of potassium iodide in water are also added. The mixture is left standing at 0 C. for 2 hours, whereby crystalline benzylpenicillin-di-n-octylaminoethyl ester-hydroiodide is formed therein. The crystals are removed from the solution by filtration. The yield of the ester-hydroiodide thereby obtained amounts to 8.75 grams which corresponds 60 per cent of the yield theoretically possible. The melting point of the esterhydroiodide is 150-152 C.

. .EXAMBIJE '.Tw-BENZYIIBENICIDLINfDIND.OD.ECYL- ..AMINOETHYL,LESTERvHYDROIODIDE I r iBy the samqproce'dure as:described in Examplefi, :using tdi-n dodecylaminoethyl chloride in place :of di-n-octylaminoethyl :chloride :as a starting material', ,benzylpeni- -:oillin-di-nrdodecylaminoethylester-hydroiodide will be ob- "itained in a yield :of 48 per cent of: the yield theoretically ipossible. The .meltingpointof: this :ester-hydroiodide ,is

170"ito:1 73 C.

EXAMPEE 8.BENZ.YLPENICILLIN-METHYDN- DGDE CYLAMINQETEYL 1E srER-HYDR OIODIDE 7.4 grams of the potassium salt of 'benzylpenicillin are 'suspen'ded-in-40 cc.--of acetone and a solution of 5.2 grams methyl-n-dodecylaminoethyl' chloride in 43.5 cc.-- benzol is added to .the.,.suspension, .whereaftenthe mixture=thus iormedjis refluxed .for 3 /2 Thours. During the reaction .therebyefiected the potassium .salt of. penicillin dissolves iand potassium-chloride. separatesfrom the solution, which .,potassium chloride is I removed by "filtration, whereafter .the .clear solution, obtained by. the filtration is evaporated .in-vacno to form asyrup. 'I'hissyrup .is dissolved in 40 cc. .acetonerand .a solution of 4.2 ,grams of themonohydrate of citric acidin 20 cc., acetoue' is added. ,A-clear solution results, which ,is diluted by 60cc. of water, after which 40 cc. of1a:IOpencentsolution of potassium iodide 'in water-are added. .The-mixtureis'left standing at C. for 4 hours whereby benzylpenicillinrmethyl- =n-dodecylaminoethyl vester-hydroiodide crystallizes from the solution and is recovered ;by filtratio.n. heyield .is 8.9 grams which corresponds to '65 per cent of the yield theoretically possible. The melting point of the esterhydroiodide is 67 to 70 C.

EXAMPLE 9.-BENZYIiPENICILLIN-DIETHYLAMINO-N- PROPYLE STER-HYDROIODIDE "The-suspension formed by adding "28;8- grams of the potassiumsalt 'of penzylpenicillin and .12 grams 'diethyl- -amino-n propyl-chlorideyto' 160 cc.-of acetone is refluxed for 12 hours. 'The reaction product thereby obtained is cooled and the cooled product contains potassium chloride 'separated during the reaction which is then removed-by filtration. A solution of 16.8'grams of the monohydrate of citric acid in 200 cc. of acetone is added to the filtrate which is then left standing for 3 hours -at "0 C. During this time benzylpenicillin diethylamino-n;propyl ester-citrate crystallizes from the solution'andis recovered by filtration, the yield being 42.7 grams which corresponds to 86 per cent of the yieldtheoretically possible. The melting point of this citrate is'-86 to 88 C.

6.4 grams of the benzylpenicillin-diethylamino-n-- propylester-citrate are dissolved in 100.cc..of waterand i1'7-.cc. .of a per cent, solution of potassiumjiodide in .watertare added. *The mixtureisJeEt to stand at 0 .C. until .the benzylpenicillin-diethylaminon-propyl esterhyfdroiodide, which forms from the two constituents of the solution, has separated, after which-.thesaid ester-hydrdiodideis recovered by filtration. "Theyield of this substance will be '4'.8 grams and1the,melting point is .142 to '1'43"* C.

-EXAMPLE 10.1BENZYLPENICILLIN-DIETHXLAMINO-N- JO'GTYLESTEREHXDR'OIODIDE Il3lfl6tgramsrof'the triethylamine.saltzofiibenzylpenicillin are dissolved in 200 cc. of dry chloroform. jA -solution of 1109 :cc.-:of:thionyl";ch1oride in .20 {(26.1 of rdry-qchloroform is added dropwise tot-thertormer solutiontduring:agitation and cooling in a refrigerating mixture in such a manner that the temperature of the reaction mixture will be maintained within the temperature limits of 10 to 8 C. The addition havingbeen completed, the resulting product is left to stand at the .said temperature for 1 hour after which-a solutionof 3.02 grams of diethylamino-n-octanol in 20 cc. of'dry chloroform is added to the reaction product and 'the-mixture-is left standing-for 1'2 hoursflthe temperature beingallowed -to increase to :20 C. The mixture thus obtained is. then subjected to extraction by '440 cc. of an aqueous solution containingiZperjcentof sodiumtcarbonatez .andrsodium bicarbonate. .The. chloroform phase is cooled by a solution; of jDry Iceuin acetone .and the -iee thereby formed is removedrby: filtration. The chloroform solution thus deprived. of its watertcontent is then evaporated in vacuo'to :dryness-'whereby"a syrup remains which is dissolved in 30 cc. of acetone. A solu- .tion; ofl 3.0::grams Dfiihfl. monohydrate :of :citric ;.ac.i;d in cc. of acetone is then added tmthe syrupandihe'mix- 10 tureuthereby formed is diluted by cc. of water after which 8 cc. of a solution containing 10 per cent potassium iodide are added. The mixture is left to stand at 0 C. for 2 .hours whereby benzylpenicillin-diethylamino-noctylester-hydroiodide separatesand isfinally removed by filtration. The .yield of this substance amounts to 4.35 gramscorresponding to 45 per cent of the yield theoreti- ,cally, possible. The melting point of the said ester- ..hydroiodide is 108to 109 C.

I areadded to the main-portion whereby amorphous benzylpenicillin-ldiethylamino-2emethylethyl ester-hydrochloride separates. By dissolvinga portion of the said esterhydrochloride in water and adding the calculated amount of potassium iodide increased by 10 per cent, the corresponding hydroiodide separates from the solution. EXAMPLE 12.BENZYLPENICILLIN-1DIETHYLAMINQ 2,2DIMETHYLETHYL 'ESTER-HYDROIODIDE 7.4 .grams of the potassium salt of benzylpenicillin are suspended in 1.00 cc. of acetone and a solution of 1.42 cc. of acetyl chloride in 25 cc. of acetoneis added dropwise to the said suspension with agitation. When the addition has been completed, 2.9 grams 1-diethylamino-2,2-dimethylethanol-(Z) are added to the resulting product. Thernixturenisthen refluxed for ,15.minutes and cooled. .Potassium chloride is thenremoved by filtration. The ,filtrate is evaporated to,25 cc..and a solution of 4.0 grams of the monohydrate ,of citric acidin 20 cc. of acetone is added'to the remainder. Now, 200 cc. of ether are added whereby the citrate of benzylpenicillin-l-diethylamino- 2,2-dimethylethyl ester separates as an amorphous substance which is removedfrom the solution by filtration and washedwithether.

6.5, grams ofthe amorphous benzylpenicillin-l-diethylamino-2.2:dimethylethyl ester-citrate are dissolved in 50 cc. of waterand 15 cc. of a solution ofpotassium iodide containing '10 per cent potassium iodide are added. The mixture is left standing at 0C. for 4 hours whereby benzylpenicillin-1=dietliylamino 2,2 dimethylethyl esterhydroiodide,separates in the crystalline form. The crystals, are removed from'the solution by filtration and the yield;of the crystalline product amounts to 4.2 grams which corresponds to 7 2 per cent of .-the yield that is theoretically possible in the reaction. The melting point of the said'ester-hydroiodide is 153 to 154 C.

EXAMPLE 13.BENZYLPENICILLIN-DIETHYLAMINO- ,ZZY-DIMETHYLPROPYL :ESTER-HYDROIODIDE :By using an equivalent amount of diethylamino-2,2- dimethylpropyl chloride in place of the 12 grams diethylamino-n-propyl chloride used in the procedure described in;the above Example 9; and using the same'procedure in all other respects, -benzylpenicillin-diethylamino-Z,2-dimethylpropyl ester-hydroiodide will be obtained. EXAMPLE 14.?BENZYLPENICILLIN-LDIETHYLAMINO- 4-METHYLBUTYL ESTER-HYDROIODIDE 7.4 grams potassium ,salt ofbenzylpenicillin are suspended in cc. of dry acetone and a solution of 1.42 cc. acetylchloride'in25 cc. acetone is added dropwise to the suspension with agitation. A reaction takes place resulting in a solution of mixed anhydride of benzylpenicillin and acetic acid. 3.2 grams 1-diethylamino-4-methylbutanolare added to this :solution after which the mixture is left standing at 20,C. for 2 hours. The amount of potassium chloride separated is removed by filtration whereafter a-solutionof,4.0 grams of the monohydrate of -citric acid-in 20-cc.-of acetone is added to the filtrate. Themixture is left; standing at 0 C. for 2 hours whereby benzylpenicillin 1 diethylamino 4 methylbutyl ester- .citrateseparates which isrecovered by filtration. The said citrate is dissolved in 50 cc. of water and 14 cc. of an, aqueous 10 per I centsolution -of potassium iodide are added. Thereby benzylpenicillin 1 diethylamino 4 methylbutyl ester-hydroiodide crystallizes from the solution and is recovered by filtration. The melting point of the ester-hydroiodide obtained is 160 to 161 C.

EXAMPLE 15.BENZYLPENICILLIN-l-DIETHYLAMINO- l-lIE'lHYL-2-ETHYLPROPL ESTER-HYDROIODIDE This substance is produced by using the general procedure described in the above Example 9, thereby replacing the 12 grams diethylamino-n-propyl chloride used as a starting material according to Example 9 by the equivalent amount of l-diethylamino-l-methyl-Z-ethylpropyl chloride.

EXAMPLE 16.-BENZYLPENICILLIN-1DIETHYLAMINO- 2,3DIETHYLBUTYL-(4) ESTER-HYDROIODIDE This compound is obtained by using the procedure described in Example 14 when in place of 3.2 grams l-diethylamino-4-methylbutanol an equivalent amount of l-diethylamino-2,3diethylbutanol-(4) is employed.

EXAMPLE 17.-BENZYLPENICILLIN-l-DI-N-BUTYLAMI- NO-2,3 DIETHYLBUTYL-(4) ESTER-HYDROIODIDE This compound is obtained by using the procedure described in the above Example 14 when in place of 3.2

grams 1-diethylamino-4-methylbutanol, an equivalent amount of 1-di-n-butylamino-2,3-diethylbutanol-(4) is em loyed.

EXAMPLE 18.BENZYLPENICILLIN-l-METHYLOCTYL- ABIINOeBUTYLPENTYL-G) ESTER-HYDROIODIDE This compound is produced by using the procedure described in the above Example 12 when in place of 2.9

grams 1 diethylamino 2,2 dimethylethanol (2) an equivalent amount of l-methyloctylamino-S-butylpentanol-(S) is employed.

EXAMPLE 19.BENZYLPENICILLIN-4-DIDODECYLA1\II- NO-4,5 DI-NPROPYLOCTYL- (5) ESTER-HYDROIODIDE This product is obtained by using the procedure described in the above Example 12 when in place of 2.9 grams 1 diethylarnino 2,2 dimethylethanol (2), an equivalent amount of 4-didodecylaniino-4,S-di-n-propyloctanol-(S is employed.

EXAMPLE 20.-BENZYLPENICILLIN-l-HEXYLDODECYL- AMINO-2,G-DIMETHYLOCTYL-(8) ESTER-HYDROIODIDE This product is obtained by using the procedure described in Example 10 when in place of 3.02 grams diethylamino-n-octanol, the equivalent amount of l-hexyldodecylamino-2,6-dimethyloctanol-(8) is employed.

EXAMPLE 21.-BENZYLPENICILLIN-DIETHYLAMINO- 2,6-DIMETHYLOCTYL-(S) ESTER-HYDROIODIDE This product is obtained by using the procedure described in Example 10 when in place of 3.02 grams diethylamino-n-octanol, the equivalent amount of diethylamino-2,6-dimethyloctanol-(8) is employed.

EXAMPLE 22.BENZYLPENICILLIN-l-DI-DODECYL- AMINO-2-EIHYL-ETHYL ESTER-HYDROIODIDE This product is obtained by using the procedure described in Example 9 when in place of 12 grams diethylamino-n-propyl chloride, an equivalent amount of 1-di-dodecylamino-2-ethylethyl chloride is employed. EXAMPLE 23.BENZYLPENICILLIN-l-DIETHYLAMINO- 2-HEXYLECLHYL ESTER-HYDROIODIDE This compound is obtained by using the procedure de scribed in Example 14 when in place of 3.2 grams l-diethylamino-4-methylbutanol, the equivalent amount of 1-diethylamino-2-hexylethanol is employed.

EXAMPLE 24.ALLYLMERCAPTOMETHYLPENICILLIN- DIETHYLAMINOETHYL ESTER-HYDROIODIDE (PENI- CILLIN-O DIETHYLAMINOETHYL ESTER-HYDROIO- DIDE) phoric acid is added that the solution takes a pH-value I of 4. A solution of 8.9 grams sodium iodide in 17 cc. of water is added dropwise to the acidified solution with agitation. The addition having been completed, the solution is left standing at 0 C. for 15 minutes, whereby allylmercaptomethylpenicillin diethylaminoethyl esterhydroiodide separates. It is then recovered by filtration, washed with 15 cc. of ice water and dried in vacuo. The yield amounts to 20 grams and the melting point of the ester-hydroiodide is 116 to 119 C. This melting point, however, can be increased to 128 to 129 C. by recrystallizing the hydroiodide first produced from a mixture of acetone and ether.

EXAMPLE 25.SUSPENSION OF BENZYLPENICILLIN- DIETHYLAMINOETHYL ESTERHYDROIODIDE IN OIL To 1 litre of peanut oil are added 20 grams of aluminum monostearate, and the mixture is heated slowly with stirring until a clear solution is obtained. The heating is continued until the solution has reached a temperature of C. at which temperature it is kept for /2-1 hour and thereafter cooled at 25 C. Then 390 grams of the hydroiodide of the diethylaminoethyl ester of penicillin G having a particle size of 2 to 5p. and a strength of 1000 units per mg. are added. The said units are determined by assaying the preparation against staphylococcus aureaus, using sodium penicillin as a standard. The final mixture contains 300, 000 international units per cc.

We claim:

1. The hydroiodide salts of aminoalcohol esters of penicillin represented by the formula:

1 Pen-CO O.R.N

where Pen-COO represents penicillin with the hydrogen atom removed from the carboxyl group; where R is alkylene containing 2 to 8 carbon atoms in a straight chain, and containing no substituent groups other than alkyl, the total number of carbon atoms in R not exceeding l4; and Where R1 and R2 are alkyl groups containing from 1 to 12 carbon atoms.

2. The compounds of claim 1, wherein the penicillin is benzylpenicillin.

3. The hydroiodide salts of aminoalcohol esters of penicillin represented by the formula:

Pen-COO.R.N

I H I R2 where Pen-COO represents penicillin with the hydrogen atom removed from the carboxyl group; where R is alkylene containing 2 to 4 carbon atoms in a straight chain, and containing no substituent groups other than alkyl, the total number of carbon atoms in such alkyl groups not exceeding 4; and where R1 and R2 are alkyl groups containing from 1 to 8 carbon atoms. 4. The compound of claim 3, wherein the penicillin is benzylpenicillin.

5. The compound of claim 3, wherein R1 and R2 are alkyl groups containing from 1 to 4 carbon atoms.

6. The compound of claim 5, wherein the penicillin is benzylpenicillin.

7. The hydroiodide salts of aminoalcohol esters of penicillin represented by the formula:

where Pen-COO represents penicillin with the hydrogen atom removed from the carboxyl group; Where R is an unsubstituted alkylene of from 2 to 3 carbon atoms; and where R1 and R2 are alkyl groups containing from 1 to 3 carbon atoms.

8. The compound of claim 7, wherein the penicillin is benzylpenicillin.

9. The hydroiodide salt of the dimethylaminoethyl ester of benzylpenicillin.

10. The hydroiodide salt of the methylethylammoethyl ester of benzylpenicillin.

11. The hydroiodide salt of the diethylaminoethyl ester of benezylpenicillin.

12. The hydroiodide salt of a methylpropylaminoethyl ester of benzylpenicillin.

13. The hydroiodide salt of an ethylpropylaminoethyl ester of benzylpenicillin.

14. An injectible therapeutic composition comprising solid particles of the compound of claim 1 suspended in an oil selected from the group consisting of vegetable and animal oils having dissolved therein a quantity of a basic salt of aluminum with a fatty acid having from 12 to 22 carbon atoms in its molecule.

15. An injectible therapeutic composition comprising solid particles of the compound of claim 7 suspended in an oil selected from the group consisting of vegetable and animal oils having dissolved therein a quantity of a basic salt of aluminum With a fatty acid having from 12 to 22 carbon atoms in its molecule.

16. The hydroiodide salts of amino alcohol esters of penicillin represented by the formula where Pen-COO represents penicillin with the hydrogen atom removed from the carboXyl group; Where R is alkyl- References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,219,796 Viaud Oct. 29, 1940 2,507,193 Buckwalter May 9, 1950 2,578,570 McDufiie et a1 Dec. 11, 1951 OTHER REFERENCES Carpenter: J. Am. Chem. 800., vol 70, (1948), pp. 2964 and 2965.

Kirchner et al.: J. Org. Chem., vol. 14, May 1949, pp. 390 to 392. 

1. THE HYDROIODIDE SALTS OF AMINOALCOHOL ESTERS OF PENICILLIN REPRESENTED BY THE FORMULA: 